Type-2 inflammation mediates olfactory loss in Chronic Rhinosinusitis: mechanisms and therapeutic opportunities

2 型炎症介导慢性鼻窦炎的嗅觉丧失：机制和治疗机会

• 批准号: 10219804
• 负责人: Bruce K Tan
• 金额: $ 59.41万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-23 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219804
• 关键词: ATP12A gene; Accounting; Adrenal Cortex Hormones; Affect; Agonist; Anosmia; Antibiotics; Biological Markers; CCL26 gene; Cell Line; Cells; Chemicals; Chronic Sinusitis; Clinical; Clinical Research; Data; Diagnostic radiologic examination; Disease Progression; Dose; Double-Blind Method; Drug Kinetics; Drug usage; Endoscopy; Enrollment; Environment; Eosinophilia; Epithelial Cells; Food; Food Selections; Formulation; Gene Expression; Genes; Genetic; H(+)-K(+)-Exchanging ATPase; Health; Human; Impairment; In Vitro; Inflammation; Inflammatory; Interleukin-13; Interleukin-4; Interleukin-5; Investigator-Initiated Research; Ion Pumps; Knock-out; Laboratories; Lansoprazole; Longitudinal Studies; Mass Spectrum Analysis; Measures; Mediating; Medical; Mentors; Methods; Mucosal Immunity; Mucositis; Mucous Membrane; Mucous body substance; Nasal Epithelium; Nasal Polyps; Nose; Olfactory dysfunction; Operative Surgical Procedures; Oral; Otolaryngology; Pathogenicity; Pathway interactions; Patient Self-Report; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Physicians; Placebos; Plasma; Porifera; Principal Investigator; Proton Pump; Proton Pump Inhibitors; Publishing; Quality of life; Randomized; Recurrence; Repeat Surgery; Research Project Grants; Risk; Sampling; Scientist; Severities; Sinus; Smell Perception; Structure of mucous membrane of nose; Surgeon; Symptoms; Testing; Therapeutic; Time; Tissues; Training; Translating; Translations; United States; United States National Institutes of Health; Universities; Visit; X-Ray Computed Tomography; airway epithelium; airway inflammation; airway surface liquid; base; chemokine; chronic rhinosinusitis; cost; cytokine; dosage; efficacy testing; eosinophil; eosinophilic inflammation; experience; experimental study; improved; increased appetite; inhibitor/antagonist; interest; novel; novel therapeutic intervention; novel therapeutics; phase II trial; professor; response; small molecule; transcriptome sequencing

Project Summary This is a request to the NIH for an Investigator-Initiated Research Project Grant (R01) for Bruce K. Tan, MD, MS, Assistant Professor of Otolaryngology at Northwestern University. The sense of smell in humans is pivotal for stimulating appetite, guiding food selection, avoiding spoiled foods and noxious chemicals, and enhancing overall quality of life. Unfortunately, many patients with chronic rhinosinusitis (CRS) suffer from extended periods of smell loss despite medical and surgical treatment. We further find that patients with type 2 inflammation of the nasal mucosa are more frequently and severely affected by smell loss before and after sinus surgery. CRS patients with type 2 inflammation are also more likely to experience recurrence of their symptoms and require repeated surgery. The Principal Investigator is a surgeon-scientist whose clinical interests focus on CRS patients but has completed extensive mentored training in mucosal immunity. This proposal seeks to translate a recent novel discovery in our laboratory that found that airway epithelial cell responses to IL-4 and -13, critical type 2 cytokines causing the most severe forms of chronic sinusitis, require action of an ion pump called the non-gastric H+/K+ATPase. Specific experiments will: (1) evaluate mechanisms by which the non-gastric H+/K+ATPase causes airway inflammation using drug inhibitors and genetic knockout cell lines; (2) evaluate how to use smell loss to accurately identify patients with active type 2 inflammation after sinus surgery; and (3) perform clinical studies to find out how to effectively use proton pump inhibitors to reduce airway eosinophilic inflammation and test whether they can reduce type 2 inflammation and improve smell function in patients with CRS. If successful, these studies will firmly establish a novel mechanism that disrupts the airway barrier in type 2 inflammatory conditions. Additionally, the results of this study may identify less invasive methods to identify type 2 inflammation in the nasal airway. Finally, the clinical studies may discover new drugs to treat persistent type 2 inflammation and smell loss in patients after sinus surgery- problems for which there are currently no effective medical treatments.

项目摘要 这是向NIH的请求调查员发动的研究项目赠款（R01） MS，西北大学耳鼻喉科助理​​教授。 人类的嗅觉对于刺激食欲，指导食物选择，避免食物是关键的 和有害的化学物质，并提高了整体生活质量。不幸的是，许多慢性患者 尽管有医学和手术治疗，但鼻鼻塞炎（CRS）仍会长期闻起来。我们 进一步发现，鼻粘膜2型炎症的患者更频繁且严重 鼻窦手术前后受气味丧失的影响。 CRS 2型炎症患者也更多 可能会经历其症状复发并需要重复手术。主要研究者是 外科医生科学家的临床兴趣专注于CRS患者，但已完成广泛的指导 粘膜免疫训练。该提议旨在翻译我们实验室中最近的小说发现， 发现气道上皮细胞对IL -4和-13的反应，至关重要的2型细胞因子，导致最严重 慢性鼻窦炎的形式需要一个称为非胃H+/K+ATPase的离子泵的作用。具体的 实验将：（1）评估非胃H+/K+ATPase引起气道的机制 使用药物抑制剂和遗传基因敲除细胞系发炎； （2）评估如何使用气味损失 准确鉴定鼻窦手术后有活性2型炎症的患者； （3）进行临床研究 找出如何有效使用质子泵抑制剂来减少气道嗜酸性炎症和测试 它们是否可以减少2型炎症并改善CRS患者的气味功能。如果成功， 这些研究将牢固建立一种新型机制，该机制破坏了2型炎症的气道屏障 状况。此外，这项研究的结果可能识别出较少的侵入性方法来识别2型 鼻气道炎症。最后，临床研究可能会发现新药物以治疗持久性2型 鼻窦手术后患者的炎症和气味损失 - 目前没有有效的问题 医疗治疗。